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It's a Small World

Scientists at KU Medical Center are focusing on the tiniest particles of life to solve some of the biggest challenges in medicine.

stylized illustration of molecules

Molecules.

It’s a word that for many people conjures up memories of high school chemistry class and the periodic table of elements that hung on the wall. But molecules are obviously so much more than that. They are the building blocks of every physical substance. They are the Lego pieces of all that’s in this world, including water and wood and air and gold and smoke and grass and milk and even the chalk dust in that classroom where we first learned about them.

And what are these building blocks made of? In a nutshell, a molecule is made of two or more atoms of elements on the periodic table — sometimes the same element, sometimes different ones — fused together by attractive forces known as chemical bonds. Single atoms of elements are not molecules. For example, a single oxygen atom is not a molecule.

But when a single oxygen atom bonds to itself (dioxygen or O2) or to another element such as carbon (carbon dioxide or CO2), a molecule is formed. Depending on way they bond, molecules can acquire distinct shapes or molecular structures such as linear, V-shaped, trigonal planar, pyramidal, trigonal pyramidal, tetrahedral, octahedral and T-shaped.

Molecules form all life, including the human body.  Most biological molecules are formed by a combination of carbon, oxygen, nitrogen and phosphorous. Some of these molecules, such as water, are small, while others, such as proteins and carbohydrates, are large and complex.

Here are just a few of the thousands of types of molecules critical to our physical selves: water molecules, which make up half the body and help cells use oxygen and nutrients; hemoglobin molecules, which are in red blood cells and transport oxygen (another crucial molecule); and adenosine triphosphate, a molecular compound synthesized in our mitochondria to store and provide energy to our cells. Perhaps the granddaddy of them all is the deoxyribonucleic acid (DNA) molecule, which carries the genetic instructions that make each of us who we are. Located in the nucleus of every cell, DNA also tells the cells to produce many types of proteins, critical workhorse molecules that perform countless tiny tasks that make the human body function.

And when biological molecules are defective, they can cause disease. Mutations in the genes responsible for putting the brakes on cell growth cause those brakes to fail, and the result is cancer. Deficiencies in enzymes that convert one chemical into another are the basis of metabolic disorders. Misfolded proteins — proteins fold into certain shapes required for their function — lead to a variety of neurogenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s.

Natural killers

Mary Markiewicz profileMary Markiewicz studies powerful immune system warriors known as T cells and natural killer (NK) cells. Both forms of white blood cells, T cells and natural killers seek and destroy abnormal or damaged cells.

Markiewicz is especially interested in a certain receptor expressed on T cells and NK cells known as NKG2D. She is looking at the role of NKG2D signaling in type 1 diabetes. People with type 1 diabetes have reduced life expectancy, and the standard of care, insulin replacement, is cumbersome. Her lab is currently testing the hypothesis that NKG2D signaling protects against type 1 diabetes by enhancing the generation of T cells.

She is also investigating how NKG2D affects the ability of natural kill cells and T cells to destroy solid tumors. Natural killer cell immunotherapy is effective against some blood cancers, but its success against solid tumors has been limited. She and her colleagues are testing the hypothesis that manipulating the expression of NKG2D can be used to increase the efficacy of natural killer cell therapy and destroy cancerous tumors.

“The more we know about how the immune system works, the more we are going to able to figure out how to manipulate it the way we want in order to fight cancer and other diseases,” Markiewicz said.

This is the business of molecular medicine, which focuses on disease causes and mechanisms at the molecular level and applies this basic research to the prevention, diagnosis and treatment of diseases and disorders. What scientists learn about how these various molecules behave to make the body function, and especially how they misbehave to cause disease, can be used to design drugs and other inventions that address those specific molecular problems.

An early example of a molecular medicine success story is the drug Herceptin, which was approved by the Food and Drug Administration (FDA) in 1998. Herceptin, which blocks a cancer-causing protein in women with breast cancer who have too many copies of a gene called HER2/neu, has turned this type of breast cancer from one of the deadliest into one of the most treatable.

In the decades since, advancements in microscopy, genetic sequencing and the ability to process and compute massive amounts of biological data promise to push molecular medicine and biology even further.

“Our ability to sequence the human genome has allowed us to determine precise defects in proteins, such as those in different types of cancer, and we can design drugs that are specifically targeted to appropriately alter the function of that protein,” said Peter Smith, Ph.D., professor of cell biology and physiology and senior associate vice chancellor for research at the University of Kansas Medical Center. “Molecular medicine holds the promise of our being able to manage health in a highly targeted manner.”

“It’s just really cool to figure out how all these cells are talking to each other,” she said. “Even when I was in high school and I got sick, I would wonder what my immune cells were doing.”

Joseph Fontes, Ph.D., a professor of biochemistry and molecular biology at KU School of Medicine, expected to follow in his father’s footsteps and become a plumber. He caught the science bug when he learned about DNA in college.

“DNA is made of just four chemical bases, four nucleotides, and from that is all the information needed to make a person. I remember thinking how can that possibly be?” he said. “Then I started learning about scientific experiments, and my interest snowballed. I liked the idea that you could understand the natural world and figure out how things work.”

Zinc fingers

Joe Fontes profileJoe Fontes’ research harkens back to his college days when he wondered how four nucleotides in DNA could make a person. He learned that it begins with gene transcription, which occurs when DNA is expressed into an RNA molecule known as messenger RNA, which contains instructions for creating proteins.

Fontes has spent decades researching a group of factors known as ZXD (Zinc Finger X-linked Duplicated) that regulate the gene transcription process in the immune system. He found that one of those factors, known as ZXDC, helps regulate genes important for the activity of myeloid cells, which are a form of white blood cells.

“These cells are kind of the first line of defense,” Fontes said. “When you get an infection, some myeloid cells, called neutrophils, attack. Other myeloid cells engulf the problem protein or virus and show it to the rest of the immune system.”

That is relevant to leukemia, which causes bone marrow to produce an excessive amount of abnormal white blood cells. Fontes’ lab showed that expressing the ZXDC protein into leukemia cells caused them to behave more like a mature, healthy myeloid cell type.

“Since a feature of many leukemias is that they are stuck in a proliferative, non-mature stage, this finding could potentially be leveraged to manage the disease,” Fontes said.

With parents who met in a research lab and five siblings who all became scientists or engineers, Liskin Swint-Kruse, Ph.D., chair of the Department of Biochemistry and Molecular Biology, isn’t sure if her career choice stems from nature or nurture. But her enjoyment of her work is obvious.

“I fell in love with proteins while I was in high school,” said Swint-Kruse, whose screensaver at KU Medical Center is an image of what she describes as a “gorgeous” protein. “Proteins are intricate little machines that carry out specialized functions, they do it exquisitely well, and trying to figure out how they carry out these functions is just fascinating to me.”

Other bench researchers, such as Danny Welch, Ph.D., professor of cancer biology, originally planned to become physicians.

“My motivation when I started working in a lab was to get a letter of recommendation so I could get into medical school,” said Welch. “What I found is that I enjoyed the research; it was so fascinating. And so that's why I went to the guy whose lab I worked in and said, ‘Would you allow me to study under your supervision?’ He gave me an opportunity. And I've been doing it now for 45 years.”

Kenneth Peterson, Ph.D., professor of biochemistry and molecular biology and an expert in genetics, also originally planned to go to medical school, until he took a microbiology course. For Peterson, solving biological puzzles is part of the fun. Microscopes help, of course, but it’s rare to be able to actually see a single molecule, Peterson noted. Researchers often instead “see” biochemical pathways indirectly, such as using antibodies that bind proteins and stains for DNA.

“That is the challenge and the elegance of biology and biochemistry research — how to infer function and pathway cascades,” Peterson said. “This type of detective work is what I love to do.”

Life at the bench

Molecular medicine relies on basic science, also known as bench science, the work done at the laboratory bench out of the view of the public. This is research conducted by the other kind of doctor: people with doctoral-level degrees in fields such as biochemistry, micro- and cell biology, physiology and pharmacology.

Form and function

Liskin Swint-Kruse profile

Proteins are made of strings of amino acids. The sequence of these acids determines the shape into which the protein folds and the function that protein performs. If a protein is altered, then its function can also change.

Liskin Swint-Kruse studies how to predict those changes and what that can mean for human health.

Computer algorithms can find these mutations and predict the outcomes, but they can only accurately predict outcomes for “conserved” amino acid positions, which haven’t been altered or mutated by evolution. Most mutations are highly detrimental, meaning they harm the function of the protein.

Swint-Kruse’s lab has found that for a subset of nonconserved positions, the rules don’t apply. Instead of being detrimental, changes at these positions can turn the function of a protein up or down like a volume control. Her lab also found that changes to amino acids at nonconserved positions don’t change what the folded protein looks like, but they do change how the protein moves.

“That motion is important,” Swint-Kruse said. “Like a car engine, the protein has lots of motions that determine how its job gets done.”

Swint-Kruse is collaborating with physicists at Arizona State University to model these motions and make predictions about how they change the protein’s function. What she learns could shed light on a person’s disease or how they might respond to different treatments.

Old concept, new tools

Before scientists were able to deepen their understanding of the biology of disease, researchers focused their work on human tissues and organs, not on the cells and molecules they’re made of.

The beginning of molecular medicine is often traced to 1949, when Linus Pauling and his colleagues discovered that the hemoglobin molecules in the red blood cells of people with sickle cell disease were different than those in healthy people. Four years later, researchers discovered the famous double-helix structure of DNA. Another seminal moment for the field happened in 2003 with the completion of the Human Genome Project, which identified and mapped the more than 20,000 genes in the human body.

“The idea of molecular medicine is not a new concept. What’s new are the tools and the ability to study things in ways that we couldn't before,” Smith said. “We’ve become more sophisticated, and we are progressively understanding things on a more molecular basis.”

When Stefan Bossmann, Ph.D., chair of cancer biology at KU Medical Center, began his training in chemistry in Germany more than 40 years ago, he and his fellow students were trained to use methods such as nuclear magnetic resonance spectroscopy to take measurements and draw conclusions about molecules and the way chemical bonds were formed. He remembers when he first saw a molecule, hexafluorobenzene, in 1980, using electron tunneling microscopy. Fortunately, it looked like he expected.

“It was a pivotal point, finding out if the methods we were taught were true,” Bossmann said. “Then we saw the molecule for the first time, and they actually were true. That was something quite spectacular.”

Today, scientists have more and better methods for unveiling the molecular world. Over the past five years, KU Medical Center has acquired two super-resolution confocal microscopes, enabling scientists to see minute cellular structures. In the spring of 2023, the medical center also became the only institution in the region to have a cryo-electron microscope (cryo-EM), which produces three-dimensional model images at nearly atomic resolution of proteins, genes, viruses and other molecules.

One thing leads to another

Danny Welch profile

Danny Welch is best-known for identifying genes associated with cancer metastasis, which accounts for 90% of cancer deaths. He discovered his first of seven metastasis suppressor genes in 1996 and named it KISS1, in honor of Hershey, Pennsylvania, then the home of his lab.

Researchers have yet to discern exactly how KISS1 functions in cancer. But they have learned that KISS1 is critical in initiating puberty and appears to be a key player in polycystic ovary disease.

“So, something that was discovered in cancer now has a role in endocrinology,” noted Welch. “Studying these molecules often leads to discoveries that can have an impact beyond where we were first looking.”

Welch also has been studying the genes in mitochondria to see if they could be important in metastasis. Working with another researcher who was studying atherosclerosis, he found that the mitochondria promoted metastasis and atherosclerosis.

After sequencing mitochondrial DNA, he and his colleagues identified a possible culprit in a molecule known as transfer RNA, which helps genes make proteins. Transfer RNA can be cleaved into fragments. Welch’s lab has been studying how these fragments are made and what their sequences are. What they could find could have implications beyond cancer.

“I think we're on the cusp of something that's going to transform how people think about how cells work, both normally as well as in disease.”

X-ray crystallography, which requires compressing the proteins or other samples into crystals, also produces intricate three-dimensional images, but some biomolecules do not crystallize because they are floppy or unstable. With cryo-EM, a protein is flash-frozen before being inserted into the microscope, where it is bombarded with electrons to form thousands of images of the molecules in various orientations. Computer software processes these images to construct a three-dimensional model of the protein.

“This technology will increase the throughput of the science and allow us to do things we couldn't do before, asking and answering questions that we hadn't been able to ask and answer before,” Smith said.

Sometimes referred to as the “resolution revolution,” this technology has enabled scientists to map the structure of the Zika virus, which can cause birth defects. It also has been used to determine the shape and make-up of plaques in the brain that are associated with Alzheimer’s disease and to decipher the unique structure that makes E. coli and other bacteria able to move.

One of the first scientist to use the new cryo-EM will be Bret Freudenthal, Ph.D., associate professor of biochemistry and molecular biology at KU Medical Center and a member of The University of Kansas Cancer Center. His lab uses cryo-EM to reveal how DNA damage is identified, removed and repaired by cellular proteins. Understanding this process at the structural level is essential to understanding the connection between DNA damage and repair and diseases such as cancer. In the past, Freudenthal and other researchers at KU Medical Center wanting to use cryo-EM imaging sent their samples to other institutions across the country and waited weeks to months for the analyses. Now, they will be able to produce images in a matter of days or even hours.

“With the new cryo-EM, we can quickly make new discoveries that we hope will lay the foundation for new therapies,” Freudenthal said. “In this way, the cryo-EM at KU Medical Center will supercharge our research program and accelerate our studies, all while training the next generation of scientists.”

The end of a genetic disease?

Ken Peterson profile

Sickle cell disease is caused by an inherited mutation in a hemoglobin molecule chain, which makes red blood cells become hard, misshapen and less able to transport oxygen. Researchers have known since the 1960s that a second mutation that turns on one of the fetal hemoglobin genes can fix a sickle crisis.

Ken Peterson wants to find a way to reactivate that fetal hemoglobin gene in sickle cell patients. His lab created a genetically altered mouse that enabled researchers to study gene expression during hemoglobin development and how the genes underlying sickle cell disease are regulated.

“We've spent years understanding the sequences of DNA that are involved in turning these genes on and off, and we've looked a lot at the proteins that bind to them and turn the genes on and off.”

Meanwhile, the first gene-editing treatment for sickle cell disease received approval from the FDA in December 2023. Using CRISPR–Cas9-based gene therapy, the treatment is a cure that corrects the sickle mutation. That’s great news, but Peterson said a simple pill to switch on the fetal hemoglobin gene is still needed. Given the basic science that has been done and the number of labs working on it, Peterson is optimistic.

“I think it could be one of the first genetic diseases to be completely wiped out.”

The new cryo-EM is housed in the electron microscopy research laboratory in the Lied building, which is near Hixson Atrium on the medical center’s Kansas City campus.

“This will be a regional resource,” said Michelle Winter, assistant dean of laboratory operations at KU Medical Center. “There is nothing else like it in the state of Kansas, and even in Missouri, it’s still very limited. We have a number of people across several institutions, including KU Medical Center, the Stowers Institute and Children's Mercy, who are ready to use this.”

The future of molecular biology

Molecular therapeutics has enabled scientists to further the field of precision medicine, in which treatments are selected for a patient on the basis of which will be most effective, and least harmful, according to that patient’s specific biology. The more scientists learn, the more precise those treatments, as well as diagnostics and vaccines, can be. Some powerful treatment regimens may combine targeted agents, which attack specific cellular or molecular defects, with conventional treatments and immunotherapies. And gene-editing technology has the potential to repair genetic defects — the root cause of disease — and profoundly improve patients’ lives.

The promise and potential of molecular biology may never have seemed more relevant than it did when vaccines were developed to fight the COVID-19 pandemic. Those vaccines were enabled by the work of two scientists in Pennsylvania, who won the 2023 Nobel Prize in Medicine for their work on the messenger RNA molecule, as well as by KU School of Medicine alumnus Barney Graham, M.D., Ph.D., whose work in structure-based vaccine design enabled the development of a vaccine that could stabilize the form-changing spike protein of the novel coronavirus and attack it before it attaches to healthy cells.

As the tools to explore the molecule become more sophisticated, molecular scientists believe there is no limit to the advances that can be made in areas as diverse as climate change, food production, artificial intelligence and, of course, medicine.

Molecular gift wrapping

Liskin Swint-Kruse profile

Stefan Bossmann’s lab at KU Medical Center creates small molecules designed to fight cancer and uses nanotechnology to figure out how to transport these molecules to the site of the tumor, while bypassing healthy tissue. That nanotechnology is what Bossmann calls his “gift wrapping business” — packaging the molecule in a structure that delivers the drugs to a specific target.

These structures, which are typically between 10 and 30 nanometers in diameter, communicate with cells and tissues they encounter along the way via attached peptides that trigger receptors on cell surfaces. This communication, known as “Eat Me” and “Don’t Eat Me” technology among scientists, tells the cancer cells to gobble up the nanoparticles loaded with the drug and tells the defensive and non-cancerous cells to leave them alone.

One of Bossmann’s current projects is working with Tomoo Iwakuma, M.D., Ph.D., at Children’s Mercy to make a molecule that binds to defective p53 proteins. The p53 protein’s job is to stop the formation of tumors. When the protein is mutated, malignant tumors can form.

“We are making a small molecule that binds preferentially to these mutants, and then kills virtually only the mutant cells,” Bossmann said. “This could be a very important tool for cancer biologists in order to develop new methods to selectively treat cancer.”

Among the molecular medicine-related discoveries that may be on the horizon are drugs that exploit or control the immune system for the treatment of cancer, autoimmune diseases and allergies; breakthroughs in regenerative medicine, including the 3D printing of living organs for clinical use; and the development of a “molecular robot” — a device that will allow carrying out “molecular surgery” to restore the damaged molecular and cellular structures of the body.

Peter Smith believes the possibilities of what the molecule can do for the advancement of medicine are boundless.

“By understanding genes, proteins and cells, we can more effectively correct the cause of disease rather than simply manage consequences.”


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