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Issue 140 Summer 2021

Endocrinologist > Summer 2021 > Features


Mini mice, football and dirty shorts

JOHN J KOPCHICK | Features



FIRST PUBLISHED IN ISSUE 61 (2001)
Human growth hormone. Credit: shutterstock

Human growth hormone. Credit: shutterstock

 

What a wonderful molecule! Its ability to cause a decrease in fat but an increase in bone and muscle amazed me. While this might seem rather ordinary to a physiologist, as a molecular biologist, I was hooked! And so, in the early 1980s, I started on my path to try and define the molecular mechanisms of growth hormone (GH) action. I am still on this journey of discovery!


The mid-1980s saw us testing the idea of different molecular ‘domains’, responsible for GH’s various activities, using altered molecules known as ‘GH analogues’. We performed classical in vitro receptor-binding studies, as structural changes were widely believed to alter a peptide hormone’s interactions with its receptor. However, I thought that a cell-based or in vivo reporter system would generate additional information – and so transgenic mice came into play. GH transgenic mice possess and express extra copies of GH genes, and are larger than their normal, non-transgenic siblings.

Alongside GH receptor (GHR)-binding studies, conducted using molecules with amino acid substitutions or deletions, we generated transgenic mice expressing the mutated DNA that encoded the GH analogues. We expected that as the in vitro binding of the GH analogues to the GHR decreased, there would be a corresponding loss of growth enhancement in the transgenic mice. This was, indeed, the case for many of the GH analogues.

GH contains four α-helices. The third has amphipathic characteristics (i.e. the charged (hydrophilic) and non-polar (hydrophobic) amino acids are separate). However, there is one hydrophilic amino acid amid the hydrophobic residues, and one hydrophobic amino acid and a glycine residue in the hydrophilic area. When we changed these three amino acids to make a ‘perfect’ amphipathic α-helix, we anticipated an increased potency of GH – a molecule that would bind GHR with higher affinity than native GH, and which would generate ‘really big mice’.

However, we found that this ‘perfect’ GH analogue bound to GHR with the same characteristics as normal GH, and therefore was no more potent than native GH. Our conviction that this perfect third α-helix should possess an altered activity fortunately drove us to generate transgenic mice that expressed this GH analogue. To our surprise, we obtained a small mouse instead of the anticipated giant! We proceeded to show that this molecule was acting as a classic antagonist. This was the first description of a large protein antagonist, and certainly the first GH antagonist.

'My years in the pharmaceutical industry had ‘drilled’ into my subconscious that anything that inhibited a physiological process in vivo could be of potential value.'

Changing the three amino acids one at a time showed that only the glycine at position 120 in human GH was important for the activity. Changing this to any amino acid other than alanine resulted in a GH molecule that inhibited growth. Thus one amino acid change out of 191 converted GH from a growth promoter to a growth suppressor or a GH antagonist.

My years in the pharmaceutical industry had ‘drilled’ into my subconscious that anything that inhibited a physiological process in vivo could be of potential value. Long hours in clinical libraries revealed three potential uses for a GH antagonist: acromegaly, diabetic end-organ damage, and certain cancers. Disappointingly, pharmaceutical companies proved unresponsive to a proposal describing our discovery.

Physical exercise provided great relief for my frustration. One of the Ohio University football coaches, the late Joe Dean, would routinely ask what I was doing in the lab. It was as we were straining on a weight-lifting machine that I told him about the lack of interest in our potential drug. He relayed to me that one of his former students and football players, Richard Hawkins, knew ‘something about drugs’. Rick was founder and CEO of a drug development company called Pharmaco, Inc. Joe scribbled Rick’s phone number on a piece of scrap paper and told me I should give him a call. It was by lucky chance that my wife subsequently rescued the very ‘clean’ piece of paper from our washing machine…

'He was incredibly excited about the GH antagonist and its potential uses, especially for acromegaly. Now, at least, there were two of us!'

Some days later, while writing an NIH proposal and day dreaming, I decided to call Rick. After an enjoyable conversation, he asked me to send my proposal. Rick subsequently read the proposal during a bout of insomnia, and recounts that he ‘could not sleep the remainder of the night’. He was incredibly excited about the GH antagonist and its potential uses, especially for acromegaly. Now, at least, there were two of us!

Together with Rick’s friend, John Scarlett, we formed a company, later called Sensus. Here, a small but extremely dedicated and competent group of individuals should be commended for the development of the GH antagonist, along with the many clinicians who performed the clinical trials for acromegalic individuals. The data show that the GH antagonist was efficacious in around 90% of these patients. The FDA is currently reviewing the data. Pharmacia Corp will market the drug, now called Somavert (pegvisomant for injection), if and when it is approved. Hopefully, it will also be tested for other indications, including cancer and diabetic end-organ damage.

So a combination of unanticipated scientific results, coupled with my interest in football, have resulted in a new drug that will benefit many individuals. I would like to acknowledge everyone who has contributed to the discovery and development of GH antagonists, in particular Wen Chen, Nick Okada, Tim Coleman, Joe Dean, Rick Hawkins, John Scarlett, Lawrence and Milton Goll, and Ohio University. This story is dedicated to the memory of Joe Dean.

JOHN J KOPCHICK
Goll–Ohio Professor of Molecular Biology, Ohio University, USA (correct at the time of first publication)




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