Billionaire investor Carl Icahn plans to nominate himself and three others to the board of Genzyme Corp , which is struggling to recover from a manufacturing crisis that lead to shortages of two of its life-saving drugs and sparked outrage from patients and investors alike.

All nine members of Genzyme's board are up for re-election at the company's annual meeting scheduled for May 20, and analysts expect at least one, and possibly more, of Icahn's nominees to be elected.

We believe the manufacturing challenges and associated impact on the business over the past year has left the Board vulnerable, said Geoff Meacham, an analyst at J.P. Morgan.

Cambridge, Massachusetts-based Genzyme, which makes drugs for rare and chronic diseases, said on Monday it will evaluate Icahn's nominees and make a recommendation that is in the best interests of all of the company's shareholders.

Icahn's challenge to Genzyme, one of the world's biggest and oldest biotech companies, comes even as he is pressing for greater control at Genzyme's cross-town rival Biogen Idec Inc , an equally venerable biotech whose multiple sclerosis drug Tysabri has been dogged by safety concerns.

Genzyme has been racing -- belatedly -- to address criticism from investors that its compensation structure was opaque, its board lacking in independence and its accounting out of step with its peers.

It recently announced an overhaul of its compensation system and added Robert Bertolini, previously chief financial officer at drugmaker Schering-Plough Corp, to its board.

The company also hired new managers to oversee quality control and agreed to appoint Ralph Whitworth of Relational Investors, another activist shareholder, to its board. In return, Whitworth agreed to support Genzyme's slate of nominees.

But Genzyme's moves may be too little too late to block Icahn, who owns 4.8 million shares, or about 1.8 percent of the company.

Investor sentiment is strongly in favor of material changes at Genzyme, said Geoff Porges, an analyst at Sanford Bernstein, in a research note. Many investors still question whether activists such as Relational have sufficient influence at Genzyme to change fundamental aspects of the company.

Genzyme's shares have fallen 22 percent over the past year, compared with a gain of 55 percent in the NYSE Arca Biotech Index.

Unlike some of its peers, whose fortunes are tied to a small handful of drugs, Genzyme has built itself into a diversified drugmaker through acquisitions.

The company's biggest-selling product is Cerezyme, a treatment for Gaucher disease that generates annual sales of more than $1 billion. Patients with Gaucher are deficient in an enzyme that breaks down certain fats in the body -- leading to organ damage and even death.

It also sells treatments for kidney disease, osteoarthritis, cancer and a product used in transplants. The company's growth-by-acquisition strategy may now have to change.

With potential board turnover, there is no guarantee that this approach would be carried forward, said Meacham. Indeed, activist focus is often toward streamlining costs and creating more strategic interest in companies as opposed to investing in fundamental business growth.

Genzyme's chief executive officer, Henri Termeer, said in a statement it has already shown it is open and responsive to shareholder input, and said we welcome a constructive dialogue with Mr. Icahn.

Icahn has not publicly outlined his strategy for Genzyme, but Whitworth has suggested in the past that Genzyme focus more tightly on its core business, which is making drugs for rare, genetic disorders, and less on costly acquisitions in unrelated areas.

Icahn has already pushed, unsuccessfully, for a sale of Biogen to a big pharmaceutical company. But concerns over the safety of Tysabri have caused potential buyers to hold back, at least for now.

Given Genzyme's many moving parts and diverse businesses, an outright sale of the company might not be the first line of attack by activists. They might rather recommend divesting businesses that have little relation to each other.

Icahn plans to nominate himself, as well as Dr. Alexander Denner, Dr. Richard Mulligan and Dr. Steven Burakoff, to Genzyme's board.

Mulligan, who is a professor of genetics at Harvard Medical School, and Denner, managing director of Icahn Partners, were elected to Biogen's board last year. They were also part of the team that ran biotechnology company ImClone Systems, which Icahn seized in 2006 and sold to Eli Lilly & Co in 2008 for $6.5 billion.

Burakoff is director of the Tisch Cancer Institute at Mount Sinai Medical Center.

Genzyme's shares were down 17 cents at $55.80 in mid-morning trading on Nasdaq.

(Reporting by Toni Clarke, editing by Dave Zimmerman and Gunna Dickson)

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