Crystal Clear

UB’s groundbreaking research in the field of crystallography comes into focus

The first high-resolution diffraction pattern results from the X-ray, free electron laser at Stanford University.

The first high-resolution diffraction pattern results from the X-ray, free electron laser at Stanford University. Photo: courtesy of Hauptman-Woodward Institute

Story by Julie Wesolowski

If you’re not in a STEM field, you probably have no idea what crystallography is. But you should, and this is why: (1) Almost every drug that’s gone on the market in the past 30 years was developed through crystallography; (2) It’s a fascinating science—in a sci-fi movie kind of way—involving the shooting of X-ray beams at crystals; and (3) UB is at the forefront of the field.

Now UB, representing a consortium of eight research universities and institutes (see “Our Partners”), is poised to make even greater strides, thanks to a prestigious $25-million award from the National Science Foundation (NSF). The award, a Science and Technology Center grant, is given out every four years and is the first of its kind for UB. Out of hundreds of applicants, UB was one of only three institutions to receive the grant; the other two recipients were Harvard and MIT.

The money will go toward the establishment of the BioXFEL research center at the Hauptman-Woodward Medical Research Institute in Buffalo (XFEL is short for “X-ray, free-electron laser”—more on that below). UB and its partner institutions will be focusing on developing X-ray bioimaging techniques—including a next-generation form of crystallography called serial femtosecond crystallography—with the ultimate goal of developing new drugs and/or other methods to treat disease.

Eaton Lattman, at the Hauptman-Woodward Medical Research Institute.

Eaton Lattman, at the Hauptman-Woodward Medical Research Institute. Photo: Douglas Levere

Crystallography: A Primer

Eaton E. Lattman, professor of structural biology, chief executive officer of the Hauptman-Woodward Medical Research Institute (HWI) and director of the BioXFEL research center, breaks down the science.

What is a crystal?
Crystals are solids that contain a repeated arrangement of millions of atoms or molecules.

What is crystallography?
Crystallography is a kind of microscopy that lets us see atoms and molecules in crystals and the distances between them. With crystallography we can make 3-D pictures of molecules so we can understand how they work.

For example, in the molecular form of water, the oxygen atom is bigger and hydrogen atoms are smaller, and it’s arranged in space like a boomerang. That’s a real picture of what a water molecule looks like.

Proteins, the big molecules that do all the work in our bodies, have thousands or tens of thousands of atoms. Each atom is connected to other atoms by little links called bonds that hold a molecule together.

Why use crystals?
We use crystals because the experiments involve shooting X-rays at the molecules. If we tried to shoot X-rays at one molecule, it would get so damaged it would never give us a picture. Since each crystal has millions of the same molecules in it, the damage gets divided up.

What happens when a crystal is X-rayed?
X-rays are a form of light that shows a very fine detail of a molecule. When the X-rays bounce off the molecules, they form a pattern. With that pattern, a picture of what’s in that molecule can be recreated.

How is crystallography involved in developing drugs?
Drugs interact with particular protein molecules in our bodies. You develop drugs by understanding the biology of a particular protein molecule and then finding a way to control that protein by designing a drug that interacts with it.

What is serial femtosecond crystallography?
In femtosecond crystallography, we X-ray a series of many small crystals until we have sampled all the orientations that we would have taken with one X-ray of a larger crystal.

We use the X-ray, free-electron laser (XFEL), an extremely powerful new kind of X-ray beam, which is actually an intense string of very short pulses. These pulses are femtoseconds long (less than a millionth of a millionth of a second), allowing us to get a picture of a crystal before it is damaged. This enables us to do experiments we couldn’t do before.

What kind of new experiments can you do?
The XFEL will let us see motions of molecules for the first time. Moving pictures will show how these proteins really work so we can understand biological processes in greater depth.

And how does that impact drug development?
Serial femtosecond crystallography will give us the ability to create more drugs at the beginning stages of the drug-development pipeline so we can design drugs without side effects. Specifically, we can observe the motions of the molecules and design a drug to bind to a target (protein) we want, while also designing it not to bind to a target we don’t want. It will also allow us to gain a new understanding of basic biological processes, which will eventually lead to new ideas about drugs.

The Challenges

As with any cutting-edge science, there are obstacles to overcome before rewards can be reaped.

According to Lattman, the biggest hurdle in crystallography is growing crystals that are large enough for experiments. It’s all trial and error—and the failure rate is 80 to 90 percent. Consequently, crystallographers spend most of their time growing the crystals rather than making the images. (See “Why It’s So Hard to Grow Crystals”)

With an XFEL beam, researchers can use crystals that are 1,000 times smaller than the crystals used now. That, says Lattman, would push the success rate above 50 percent. However, femtosecond crystallography brings its own set of challenges.

For one, there’s only one XFEL laser in the world, and it’s not in Buffalo. It’s in a lab at Stanford University in California, and competition for its use—from researchers in a whole range of fields—is stiff. UB’s track record with femtosecond crystallography hasn’t helped matters. “We’ve been so successful that there are other people in the field who want to use it too,” Lattman says.

Other complications involve learning how to grow the tiny crystals (though it’s easier than growing large crystals, it’s still a difficult process), shipping them across the country and getting them into the beam at the right time. At this point, researchers are far from solving any of these issues. On the plus side, HWI’s decades of expertise in X-ray crystallography clearly convinced the NSF that if anyone can figure it out, they can.

Why It’s So Hard to Grow Crystals

Crystals are a complicated business. Dr. Lattman explains why.

"At this moment growing crystals is a trial-and-error process. This is because each protein is different, so that the recipe for one does not work for the next. Our steps in growing are:

  1. Dissolve the protein, usually in a solution that contains water and small amounts of other chemicals.
  2. Add something to the protein solution that makes the protein less soluble. These additives are quite varied, and range from salt to organic polymers. When the solubility is reduced, the protein ‘comes out.’ It might fall out as a crystal, but much more often it comes out as an amorphous precipitate also known as ‘glop.’
  3. Try steps 1 and 2 in hundreds of different combinations hoping to luck out."
The Hauptman-Woodward Medical Research Institute.

The Hauptman-Woodward Medical Research Institute. Photo: Douglas Levere

Where It All Began

A rich history in crystallography research made Buffalo’s Hauptman-Woodward Medical Research Institute an obvious choice for the BioXFEL research center. Below is a brief history.

Early beginnings: 1956
Originally called the Medical Foundation of Buffalo (MFB), HWI gets its start through the combined efforts of endocrinologist and medical researcher George F. Koepf and his patient and benefactor Helen Woodward Rivas.

Recruiting a visionary: 1970
Herbert Hauptman is recruited from the U.S. Naval Research Laboratory in Washington, D.C., to the Medical Foundation of Buffalo. He also joins UB’s biophysical sciences faculty. In 1972, he becomes research director of MFB.

Herbert Hauptman.

Herbert Hauptman. Photo: Mark Dellas

Nobel Prize: 1985
Hauptman and Jerome Karle of the U.S. Naval Research Laboratory jointly win the Nobel Prize in chemistry for essentially inventing crystallography. Hauptman is the only person to have received the Nobel Prize while living in Western New York.

A new identity: 1994
The Medical Foundation of Buffalo is renamed Hauptman-Woodward Medical Research Institute in honor of early benefactor Helen Woodward Rivas and Nobel Laureate Herbert Hauptman.

The 21st century and beyond
Since 2001, HWI functions as the Department of Structural and Computational Biology for UB. It typically trains a dozen PhD students every year.

HWI also houses the American Crystallographic Association, which boasts a membership of 2,200 scientists from more than 60 countries spanning the globe.

Its legacy    
HWI scientists have crystallized and determined the structure of more than 300 steroid hormones, 100 thyroid hormones, 50 ion-transport antibiotics, 30 prostaglandins and hundreds of additional compounds, including proteins and enzymes implicated in diseases.

Applying the Grant: From Coast to Coast

While most of the administration of the grant will take place in Buffalo at the BioXFEL research center, UB and its seven partner institutions across the country will collaborate on the NSF grant to do the following:

  • Determine new research processes and create the infrastructure to analyze molecules using the XFEL
  • Aim to increase success rates in growing crystals that are 1,000 times smaller than the crystals previously used
  • Find a way to transport the crystals to the Stanford laboratory where the XFEL is located
  • Perfect the method of loading the crystals into the XFEL for experimentation
  • Design computer software to analyze the new femtosecond crystallography patterns

Recruiting Tomorrow’s Researchers

Margarita L. Dubocovich.

Margarita L. Dubocovich, chair of pharmacology and toxicology and senior associate dean for inclusion and cultural enhancement at UB, will direct the BioXFEL educational program. With two of its partner universities, the University of Wisconsin-Milwaukee and Arizona State University, UB will recruit graduate, undergraduate and high school students to get involved in the field of molecular biology through newly created educational programs.

The Ripple Effect

As one of only three universities to receive the Science and Technology Center grant, UB’s academic image in the field of molecular research is getting a major boost. That will have an impact on UB’s ability to recruit faculty and students, and to attract new technology companies to the Buffalo Niagara region. Additionally, Lattman and his colleagues are already planning for other grant opportunities that will supplement research borne of the BioXFEL center

Our Partners

Arizona State University

Cornell University

Rice University

Stanford University

UC Davis

University of California, San Francisco

University of Wisconsin-Milwaukee

Julie Wesolowski is a Buffalo-based writer and digital communications professional.