College of Agricultural and Life Sciences

College of Agricultural and Life Sciences

Above ↑ Eighteen-month-old Isabella Stanley waits on the lap of her father, Don, as physician Debra Macleish prepares to administer a therapeutic dose of botulinum toxin. Due to a condition called hemiparisis, Isabella has tightness in muscle groups that makes it difficult for her to open her left hand or rotate her left arm. Combined with physical and occupational therapy, Botox® treatments help relax the muscles and give Isabella more sensory response. “It’s really made a major difference for her,” says Don Stanley

It’s not about the wrinkles

Home >> It’s not about the wrinkles

A half-century of research helped harness the world’s deadliest toxin to treat serious health problems

Throughout history, botulism has been a feared, often fatal form
of food poisoning. Today botulinum toxin is a pharmaceutical Swiss Army knife with dozens of therapeutic applications.

Physicians administer millions of cosmetic Botox® injections a year in the United States for facial wrinkles, but the drug’s uses extend far beyond pretty faces.

A summer 2005 query for “Botox therapeutic” on the National Library of Medicine’s PubMed search engine returned 1,358 research articles involving non-cosmetic uses of Botox for a broad range of ailments. Much of this research is based on work done at the College’s Food Research Institute (FRI), where the late Ed Schantz pioneered botulinum research. After earning a Ph.D. in biochemistry at the UW-Madison, during World War II Schantz explored ways to protect people against botulinum and other potential biological weapons. He continued his research after the war and returned to Madison in 1972. In 1979, he prepared a specially purified batch of botulinum for the first trials with human volunteers.

In 1985, Eric Johnson came to the institute from Harvard Medical School to begin a research collaboration with Schantz that would last until Schantz died in April 2005.

In 1989, Johnson and Schantz made more batches of purified toxin, and botulinum toxin was licensed as an orphan drug for certain facial muscular disorders — strabismus, blepharospasm and hemifacial spasm. From 1989 until 1997, much of the therapeutic botulinum toxin used in the United States came from FRI labs.

Johnson’s botulinum research interests range from basic to applied. They include purification and stabilization of toxin, characterization, physiology and genetics of Clostridium botulinum, interspecies transfer of the gene coding for toxins, regulation of expression of toxins and behavior and control of C. botulinum in foods.

On the bioterrorism A-list

Working with colleagues at the UW-Madison and other universities, Johnson currently has nine grant-funded projects investigating botulinum. Many deal with bioterrorism defense.

“In terms of biosecurity, botulinum is on the ‘Category A’ list, along with smallpox, Ebola and anthrax because it’s the most poisonous toxin known,” he says.

This work deals with means of detecting the toxin, such as remote sensing to trigger an alarm if the toxin is dispersed in a public place. It also looks at countermeasures — for example, antibody and therapeutic delivery for deliberate (or accidental) exposure that would neutralize toxin that has entered the bloodstream. Right now, there’s no antidote if fatal levels of toxin reach nerves. Johnson and his colleagues are also looking at improved vaccines and countermeasures.

C. botulinum has had its share of scientific attention over the years, but it still holds surprises for researchers.

“We’re finding that there is much more diversity in the organism and the toxin than we first thought,” Johnson says. “Our lab makes all seven serotypes. The Food Research Institute has worked with botulinum for about 50 years, and we have a lot of strains and the resources for studying all aspects of the toxins.

“The structure of botulinum has given all kinds of hints about how it works. We’re trying to understand more of the toxin’s biology, which might let us develop toxins with longer (or shorter) durations, better targeting, and other desired clinical attributes,” he says.

Some patients have developed immunity to the toxin after long-term treatments. Johnson’s lab is working on second-generation toxins that may help prevent immunity and side effects such as diffusion to neighboring muscles.

Beyond pretty faces

In addition to its well-publicized cosmetic uses (accounting for an estimated 30 percent of Botox® sales) and its original applications as an orphan drug, physicians use botulinum toxin to treat many other afflictions:

• Dystonias — involuntary muscle contractions, including jaw-closure dystonia and related dental problems
• Urologic problems, including overactive bladder, pelvic floor spasticity, interstitial cystitis and prostatitis
• Spasticity from strokes, cerebral palsy and multiple sclerosis
• Tremors tied to Parkinson’s disease
• Rheumatoid arthritis
• Orthopedic applications that require muscle immobilization
• Pain syndromes
• Stuttering, voice tremors and other vocal cord problems

The list grows every year. Botulinum has utility in the treatment of a number of diseases that for many years were untreatable by other methods,” Johnson says. “We’re finding that many difficult-to-diagnose ailments are actually tractable to botulinum treatments. Botulinum toxin is now the primary drug for their treatment.”

The toxin offers several unique advantages. Unlike many drugs, it targets specific problem muscles. It can be administered during office visits and relieves symptoms relatively quickly. And, unlike surgery, botulinum treatments leave no scars and require no healing period.

Its effects are reversible — which is both a plus and a minus. Unlike many toxins, it doesn’t destroy cells or permanently damage tissues, but patients require retreatment after the effects wear off.

Johnson says about 40 labs worldwide now use botulinum as a tool to understand cellular biology and about 10 labs are doing basic research on C. botulinum and its toxins.

Metabiologics, Inc., an offshoot company from Johnson’s laboratory and FRI, makes and sells all seven serotypes of botulinum toxin for use by accredited researchers worldwide. The company produces botulinum toxins, toxoids and antibodies, along with assay standards and assay kits for detection of botulinum toxin. The company has provided botulinum toxins for basic research and for development of countermeasures by the government and private industry.

“Natural toxins affect human physiology by widely diverse mechanisms. The remarkable success of botulinum neurotoxin as a therapeutic has helped create a new field in the development and utilization of microbial toxins as drugs to treat human diseases,” Johnson says. “Research is underway to use clostridial toxins or subparts for drug delivery, prevention of food poisoning, and treatment of cancer and other diseases. Continued basic and applied research on microbial toxins should enable researchers to develop many of these toxins for beneficial human purposes.”